EP1973952A1 - Conjugué comprenant un composé pharmaceutiquement actif lié de façon covalente à un polymère mucoadhésif et méthode d'administration transmucosale de composé pharmaceutiquement actif faisant appel audit conjugué - Google Patents

Conjugué comprenant un composé pharmaceutiquement actif lié de façon covalente à un polymère mucoadhésif et méthode d'administration transmucosale de composé pharmaceutiquement actif faisant appel audit conjugué

Info

Publication number
EP1973952A1
EP1973952A1 EP07701046A EP07701046A EP1973952A1 EP 1973952 A1 EP1973952 A1 EP 1973952A1 EP 07701046 A EP07701046 A EP 07701046A EP 07701046 A EP07701046 A EP 07701046A EP 1973952 A1 EP1973952 A1 EP 1973952A1
Authority
EP
European Patent Office
Prior art keywords
chitosan
active substance
conjugate
pharmacologically active
linker
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07701046A
Other languages
German (de)
English (en)
Other versions
EP1973952A4 (fr
Inventor
Sang Yong Jon
Eun Hye Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gwangju Institute of Science and Technology
Original Assignee
Gwangju Institute of Science and Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020060068804A external-priority patent/KR100766820B1/ko
Priority claimed from KR1020060068801A external-priority patent/KR100791414B1/ko
Application filed by Gwangju Institute of Science and Technology filed Critical Gwangju Institute of Science and Technology
Publication of EP1973952A1 publication Critical patent/EP1973952A1/fr
Publication of EP1973952A4 publication Critical patent/EP1973952A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins

Definitions

  • the present invention relates to a conjugate comprising a pharmacologically active substance covalently bound to a mucoadhesive polymer and a method for transmucosal delivery of a pharmacologically active substance using the same.
  • biopharmaceutical products e.g. biopharmaceutical products (hereinafter, also referred to as "biodrugs")
  • biodrugs biopharmaceutical products
  • proteins exhibit non-absorptive tendencies through the mucous membranes of organisms due to huge molecular weight and specific molecular structure, thereby suffering from difficulties in application thereof for oral preparations. Therefore, an administration route of proteins is confined to injection, which is accompanied by various problems, such as difficulty of medication upon chronic administration of drugs and fear and rejection of injection therapy to patients.
  • P-gp P- glycoprotein
  • CsA cyclosporin A
  • Valspodar cyclosporin A
  • Transmucosal delivery is a method for administration of pharmacologically-active substance and provides great advantages. Owing to an ability of transmucosal delivery that can achieve systemic and local drug effects on target sites, the transmucosal delivery system has received a great deal of attention as an attractive drug delivery system which can cope with specific regimens of drugs. Transmucosal delivery not only rapidly exerts therapeutic effects but also exhibits rapid drug clearance, consequently increasing bioavailability of the drug. In addition, the transmucosal delivery system is superior in patient medication compliance, as compared to other administration methods.
  • 5554388 discloses a composition for administration to the mucosa which comprises a pharmacologically active compound and a polycationic substance.
  • US Patent No. 6,913,746 describes complexes consisting of immunoglobulins and polysaccharides for oral and transmucosal use
  • US Patent Application No. 2005/0175679 Al describes a composition for transmucosal administration, comprising morphine and a water-soluble polymer.
  • the inventors of the present invention have made many efforts to develop a drug delivery system that can realize transmucosal delivery, particularly oral transmucosal delivery of drugs while overcoming side effects and disadvantages which were suffered by conventional drug delivery systems of pharmacologically active substances.
  • the inventors of the present invention have surprisingly discovered that it is possible to elicit excellent pharmacological efficacy of desired drugs in vivo by selection of a mucoadhesive polymer, exhibiting an excellent in vivo mucosal absorption rate, safety and in vivo degradability, as a delivery system capable of achieving the above-mentioned purposes, and oral administration of a conjugate comprising a pharmacologically active substance covalently bound to the thus-selected mucoadhesive polymer.
  • the present invention has been completed based on these findings.
  • the present invention has been made in view of the above problems, and it is an object of the present invention to provide a conjugate comprising a pharmacologically active substance and a mucoadhesive polymer covalently bound to each other via a linker.
  • a conjugate comprising a pharmacologically active substance and a mucoadhesive polymer covalently bound to each other via a linker.
  • a pharmaceutical composition for transmucosal administration of a drug comprising the aforementioned conjugate and a pharmaceutically acceptable carrier.
  • the conjugate of the present invention exhibits excellent absorption rate and bio- compatibility in biological mucous membranes, particularly mucous membranes of alimentary canal (especially the gastrointestinal tract), in vivo degradability, and superior bioavailability even with oral administration, thus enabling treatment of diseases via oral administration of a drug.
  • FIG. 1 is a graph showing changes in the relative blood glucose levels of animals after intravenous injection of an insulin-chitosan conjugate of the present invention into the tail veins of diabetes -induced male rats;
  • FIG. 2 is a graph showing changes in the relative blood glucose levels of animals after oral administration of an insulin-chitosan conjugate solution of the present invention to diabetes -induced male rats;
  • FIG. 3 is a bar graph showing results of MTT assay for cytotoxic effects of a paclitaxel-chitosan conjugate of the present invention on tumor cells.
  • Black paclitaxel; Diagonal line: paclitaxel-chitosan (MW: 3000) conjugate of the present invention;
  • White paclitaxel-chitosan (MW: 6000) conjugate of the present invention;
  • FIG. 4 is a graph showing analysis results of allograft experiments for in vivo anticancer effects of a paclitaxel-chitosan conjugate of the present invention.
  • FIG. 5 is a graph showing a survival rate of animals after oral administration of a paclitaxel-chitosan conjugate to mice. Best Mode for Carrying Out the Invention
  • pharmacologically active substance refers to a protein or peptide having pharmacological activity or a functional equivalent compound thereof.
  • the pharmacologically active substance includes recombinantly, or synthetically synthesized substances, and other substances isolated from nature.
  • protein refers to a polymer of amino acids in peptide linkages and the term peptide refers to an oligomer of amino acids in peptide linkages.
  • Examples of the protein or peptide that is used as the pharmacologically active substance in the present invention may include, but are not limited to, hormones, hormone analogues, enzymes, enzyme inhibitors, signaling proteins or fragments thereof, antibodies or fragments, single-chain antibodies, binding proteins or binding domains thereof, antigens, attachment proteins, structural proteins, regulatory proteins, toxin proteins, cytokines, transcriptional regulatory factors, blood coagulation factors, and anti-cancer drugs.
  • the pharmacologically active substance of the present invention may include materials that can be used as a protein drug, for example insulin, insulin-like growth factor 1 (IGF-I), growth hormones, interferons (IFNs), erythropoietins, granulocyte-colony stimulating factors (G-CSFs), granulocyte/ macrophage-colony stimulating factors (GM-CSFs), interleukin-2 (IL-2) or epidermal growth factors (EGFs). More preferred is insulin or IGF-I. Most preferred is insulin.
  • IGF-I insulin-like growth factor 1
  • IFNs interferons
  • IFNs interferons
  • IFNs interferons
  • erythropoietins erythropoietins
  • G-CSFs granulocyte-colony stimulating factors
  • GM-CSFs granulocyte/ macrophage-colony stimulating factors
  • IL-2 interleukin-2
  • EGFs epi
  • the pharmacologically active substance of the present invention may include any anti-cancer drug that is used as an anti-cancer chemotherapeutic agent, for example preferably cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosourea, Dactinomycin (actinomycin-D), daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, paclitaxel, transplatinum, 5-fluorouracil, adriamycin, vincristine, vinblastine and methotrexate. Most preferred is paclitaxel.
  • mucoadhesive polymer refers to a polymer having a good in vivo mucosal absorption rate, safety and degradability.
  • the mucoadhesive polymer used in the present invention may be synthesized or may be naturally-occurring materials.
  • Examples of naturally-occurring mucoadhesive polymers may include, but are not limited to, chitosan, hyaluronate, alginate, gelatin, collagen, and derivatives thereof.
  • Examples of synthetic mucoadhesive polymers may include, but are not limited to, poly(acrylic acid), poly(methacrylic acid), poly( -lysine), poly(ethylene imine), poly (2-hydroxy ethyl methacrylate), and derivatives or copolymers thereof.
  • the mucoadhesive polymer of the present invention may be chitosan.
  • Chitosan is made by deacetylation of chitin.
  • chitin is one of the most abundant organic polymers in nature, with as much as ten billion tons of chitin and its derivatives estimated to be produced from living organisms each year.
  • Chitin is quantitatively found in the epidermis or exoskeletons of crustaceans such as crabs and shrimps and insects such as grasshoppers and dragonflies, and in the cell walls of fungi, mushrooms such as Enoki Mushroom (Flammulina velutipes) and Shiitake mushrooms (Lentinus edodes) and bacteria.
  • chitin is a linear polymer of beta 1-4 linked N-acetyl-D-glucosamine units composed of mucopolysaccharides and amino sugars (amino derivatives of sugars).
  • Chitosan is formed by removal of acetyl groups from some of the N-acetyl glucosamine residues (Errington N, et al., Hydrodynamic characterization of chitosan varying in molecular weight and degree of acetylation. Int J Biol Macromol. 15:1123-7 (1993)). Due to removal of acetyl groups that were present in the amine groups, chitosan is present as polycations in acidic solutions, unlike chitin.
  • chitosan is readily soluble in an acidic aqueous solution and therefore exhibits excellent processability and relatively high mechanical strength after drying thereof. Due to such physicochemical properties, chitosan is molded into various forms for desired applications, such as powders, fibers, thin films, gels, beads, or the like, depending desired applications (E. Guibal, et al., Ind. Eng. Chem. Res., 37:1454-1463 (1998)). Chitosan is divided into a chitosan oligomer form composed of about 12 monomer units and a chitosan polymer form composed of more than 12 monomer units, depending upon the number of constituent monomer units.
  • the chitosan polymer is subdivided into three different types, low-molecular weight chitosan (LMWC, molecular weight of less than 150 kDa), high-molecular weight chitosan (HMWC, molecular weight of 700 to 1000 kDa), and medium-molecular weight chitosan (MMWC, molecular weight between LMWC and HMWC).
  • LMWC low-molecular weight chitosan
  • HMWC high-molecular weight chitosan
  • MMWC medium-molecular weight chitosan
  • chitosan Due to excellent stability, environmental friendliness, biodegradability and biocom- patibility, chitosan is widely used for a variety of industrial and medical applications. Further, it is also known that chitosan is safe and also exhibits no immunoenhancing side effects. The in vivo degradation of chitosan molecules by lysozyme produces N- acetyl-D-glucosamine which is used in the synthesis of glycoproteins and finally excreted in the form of carbon dioxide (CO ) (Chandy T, Sharma CP. Chitosan as a biomaterial. Biomat Art Cells Art Org. 18:1-24 (1990)).
  • CO carbon dioxide
  • Chitosan that can be used in the present invention may include any type of chitosan conventionally used in the art.
  • Chitosan of the present invention has a molecular weight of preferably 500 to 20000 Da, more preferably 500 to 15000 Da, particularly preferably 1000 to 10000 Da, and most preferably 3000 to 9000 Da. If the molecular weight of chitosan is lower than 500 Da, this may result in poor function of chitosan as a carrier. On the other hand, if the molecular weight of chitosan is higher than 20000 Da, this may lead to a problem associated with formation of self-aggregates in an aqueous solution.
  • the preferred chitosan used in the present invention is oligomeric chitosan.
  • the conjugate of the present invention is characterized in that the pharmacologically active substance and the mucoadhesive polymer are covalently bound to each other via a linker.
  • the covalent bonding between the pharmacologically active substance of the present invention and the mucoadhesive polymer may be formed depending upon various kinds of bonds.
  • Examples of covalent bonds may include disulfide bonds, peptide bonds, imine bonds, ester bonds and amide bonds.
  • the covalent bonding is formed largely by two types: direct bonding and indirect bonding.
  • a covalent bond may be formed by direct reaction of a functional group (for example, -SH, -OH, -COOH, and NH ) on the pharmacologically active substance with a functional group (for example, -OH and -NH ) on the mucoadhesive polymer.
  • a functional group for example, -SH, -OH, -COOH, and NH
  • the pharmacologically active substance-mucoadhesive polymer complex may be formed by the medium of a compound conventionally used as a linker in the art.
  • the conjugate of the present invention is covalently bound via the linker.
  • the linker used in the present invention may be any compound that is conventionally used as a linker in the art.
  • the linker may be appropriately selected depending upon kinds of the functional groups present on the pharmacologically active substance.
  • linker may include, but are not limited to, N-succinimidyl iodoacetate, N-hydroxysuccinimidyl bromoacetate, m-maleimi- dobenzoyl-N-hydroxysuccinimide ester, m-maleimi- dobenzoyl-N-hydroxysulfosuccinimide ester, N-maleimidobutyryloxysuccinamide ester, N-maleimidobutyryloxy sulfosuccinamide ester, E-maleimidocaproic acid hydrazideDHCl, [N-(E- maleimidocaproyloxy)-succinamide] , [N-(E-maleimidocaproyloxy)-sulfosuccinamide], maleimidopropionic acid N- hydroxysuccinimide ester, maleimidopropionic acid N-hydroxysulfosuccinimide ester, maleimidopropi
  • the covalent bonding of the protein or peptide and chitosan involves interposition of the linker of -CO-(CH 2 ) n -
  • n is an integer of 1 to 5.
  • the conjugate of the protein or peptide (e.g. insulin) and chitosan has a structure wherein -CO-(CH ) -S-S-(CH ) -CO- is interposed between two components and -NH of chitosan and -NH of the protein are respectively covalently bound to the linker via the amide bond.
  • covalent bonding of an anti-cancer drug and chitosan involves interposition of a succinyl group therebetween.
  • the succinyl group and chitosan forms an amide bond
  • the succinyl group and the anti-cancer drug forms an ester bond.
  • CH -CO- is interposed between the anti-cancer drug (e.g. paclitaxel) and chitosan, and the succinyl group and chitosan are covalently bound to each other via the amide bond.
  • anti-cancer drug e.g. paclitaxel
  • succinyl group and chitosan are covalently bound to each other via the amide bond.
  • the conjugate of the present invention is characterized by being capable of delivering the pharmacologically active substance via transmucosal routes.
  • administration routes for transmucosal delivery of the conjugate may include, but are not limited to, mucous membranes of buccal cavity, nasal cavity, rectum, vagina, urethra, throat, alimentary canal, peritoneum and eyes.
  • the conjugate of the present invention enables oral administration of the drug by delivery of the pharmacologically active substance via a mucous membrane of the alimentary canal.
  • the present invention also provides a pharmaceutical composition for transmucosal administration of a drug, comprising a therapeutically effective amount of the conjugate of the present invention and a pharmaceutically acceptable carrier.
  • therapeutically effective amount refers to an amount enough to achieve inherent therapeutic effects of the pharmacologically active substance.
  • tharmaceutically acceptable refers to a formulation of a compound that is physiologically acceptable and does not cause allergic response or similar response such as gastric disorder, vertigo, and the like, when it is administered to a human.
  • the pharmaceutically acceptable carrier may be a material that is conventionally used in preparation of a pharmaceutical formulation.
  • the pharmaceutically acceptable carrier may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydrox- ybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention may further comprise a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative or the like. Details for formulation and suitable pharmaceutically acceptable carriers may be found in Remington's Pharmaceutical Sciences(19th ed., 1995).
  • the pharmaceutical composition of the present invention is characterized in that it is administered via transmucosal routes.
  • administration routes for transmucosal delivery of the composition may include, but are not limited to, buccal, nasal, rectal, vaginal, urethral, throat, alimentary canal, peritoneal and ocular mucosae.
  • the pharmaceutical composition of the present invention enables oral administration of the drug by delivery of the pharmacologically active substance via the alimentary canal mucosa.
  • a suitable dose of the pharmaceutical composition of the present invention may vary depending upon various factors such as formulation method, administration mode, age, weight and sex of patients, pathological conditions, diet, administration time, administration route, excretion rate and sensitivity to response.
  • the composition is administered at a dose of preferably 0.001 to 100 mg/kg BW/day.
  • the pharmaceutical composition of the present invention may be formulated into a unit dosage form, or may be prepared in the form of a multi-dose form, using a pharmaceutically acceptable carrier and/or excipient.
  • the resulting formulation may be in the form of a solution, suspension or emulsion in oil or an aqueous medium, or otherwise may be in the form of an extract, a powder, a granule, a tablet or a capsule.
  • the formulation may additionally comprise a dispersant or a stabilizer.
  • the present invention provides a pharmaceutical composition for oral administration of insulin, comprising (a) a conjugate comprising a therapeutically effective amount of insulin covalently bound to chitosan, and (b) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition for treatment of diabetes according to the present invention enables oral administration of insulin. Generally, diabetic patients are given an insulin injection. Such an administration method is very inconvenient to patients in several aspects. However, the pharmaceutical composition for treatment of diabetes according to the present invention may lead to remarkable improvement in diabetic treatment regimens due to the possibility of oral administration.
  • the insulin-chitosan conjugate of the present invention exhibits an excellent absorption rate through a mucous membrane (particularly, the gastrointestinal mucosa).
  • the pharmaceutical composition of the present invention provides a pharmaceutical composition for oral administration of paclitaxel, comprising (a) a conjugate comprising a therapeutically effective amount of paclitaxel covalently bound to chitosan, and (b) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprising the paclitaxel-chitosan conjugate of the present invention exerts an excellent anti-cancer effects even by transmucosal administration, particularly oral transmucosal administration..
  • the paclitaxel-chitosan conjugate of the present invention exhibits an excellent absorption rate from a mucous membrane (particularly, gastrointestinal mucous membrane).
  • the present invention provides a method for in vivo delivery of a pharmacologically active substance via a transmucosal route, by covalent binding of the active ingredient with a mucoadhesive polymer via a linker.
  • the method of the present invention comprises (a) binding the pharmacologically active substance to the linker, and (b) conjugating the pharmacologically active substance of Step (a) with the mucoadhesive polymer via the linker.
  • the method of the present invention comprises (a) binding the pharmacologically active substance to the linker, (b) binding the linker to the mucoadhesive polymer, and (c) conjugating the pharmacologically active substance of Step (a) with the mucoadhesive polymer of Step (b) via the linker.
  • the conjugate of the present invention exhibits an excellent absorption rate in biological mucous membranes, particularly mucous membranes of the alimentary canal (especially the gastrointestinal tract). [79] (ii) Because the mucoadhesive polymer used as the carrier of a target drug is highly biocompatible and biodegradable in vivo, the conjugate of the present invention is safe and also exhibit excellent safety even with chronic administration.
  • the pharmaceutical composition of the present invention exhibits superior bioavailability even upon oral administration, thus making it possible to achieve treatment of diseases via oral administration.
  • the aforementioned mixed solution was adjusted to a range of pH 9 to 10 using aqueous NaOH and stirred at room temperature for 30 min.
  • the resulting stirred solution was subjected to reverse-phase HPLC (Shimadzu) separation and freeze-drying (lyophilization) to thereby prepare an insulin intermediate product (see Reaction Scheme 1).
  • Example 3 Construction of insulin-chitosan conjugate [95]
  • 0.008 g (1.24x10 -v- " 6° mol) of the chitosan intermediate prepared in Example 2 and 0.3 mL of DTT (24.9 xlO mol) (Pierce) were dissolved in 0.3 mL of PBS and stirred at room temperature for 4 hours.
  • 0.005 g (0.83x10 mol) of the insulin intermediate prepared in Example 1 was dissolved in a citrate buffer solution (500 D), the reduced chitosan intermediate solution (100 D) was added thereto, and the resulting mixture was stirred at room temperature for 12 to 24 hours.
  • the stirred mixture was subjected to reverse-phase HPLC separation and freeze- drying to thereby prepare an insulin-chitosan conjugate (see Reaction Scheme 2).
  • an amount of insulin contained in an insulin-chitosan conjugate of the present invention (a conjugate using chitosan of MW 6000)
  • 1 mg of the insulin-chitosan conjugate was dissolved in 1 mL of a citrate buffer solution and an absorbance was measured at a wavelength of UV 275 nm.
  • the standard curve was plotted by dissolving insulin (0.1, 0.5, 1 and 2 mg) in 1 mL of a citrate buffer solution and measuring the absorbance at the given wavelength.
  • the amount of insulin contained in the insulin-chitosan conjugate was calculated. As a result, the content of insulin in the conjugate was 44%.
  • An insulin-chitosan conjugate of the present invention (a conjugate using chitosan of MW 6000) was dissolved in a citrate buffer solution and then diluted with physiological saline to prepare an insulin-chitosan conjugate solution at an insulin concentration of 1 U/mL.
  • Diabetes-induced male Wistar rats (6 to 7-weeks old) were fasted for 6 hours prior to administration of insulin, and blood was collected from the tail veins of the animals and the blood glucose level was determined. The thus- obtained value was used as an initial value.
  • a 0.5 IU/kg insulin- or 1 IU/kg insulin-chitosan conjugate (Insulin-6K LMWC) was intravenously injected to the tail veins of the animals.
  • 0.5 IU is equivalent to 17.4 D of insulin.
  • animals were given subcutaneous (s.c.) injection of 0.5 IU/kg insulin (control).
  • An insulin-chitosan conjugate (a conjugate using chitosan of MW 3000, 6000 or
  • an experimental group of rat with administration of the insulin- chitosan conjugate solution of the present invention at a dose of 50 IU insulin/kg exhibited more than a 40% decrease in the blood glucose level 2 hours later, as compared to the initial blood glucose level.
  • animal groups with oral administration of insulin-free saline, insulin itself and chitosan itself exhibited no lowering of the blood glucose levels.
  • Example 5 Construction of paclitaxel-chitosan conjugate [127] 0.1 g (0.105x10 mol) of a paclitaxel/succinic acid derivative, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (Sigma) and N- hydroxysuccinimide (NHS) (Sigma) were dissolved in 3 mL of DMF, and the resulting mixture was stirred at room temperature for 4 hours (see Reaction Scheme 3).
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • NHS N- hydroxysuccinimide
  • 0.2 g (66.67xlO "6 mol) of chitosan of MW 3000 and 6000 (KITTOLIFE, Co., Ltd., Seoul, Korea) was dissolved in a borate buffer solution (3 mL) and DMF (9 mL), which was then added to the above stirred solution and stirred at room temperature for 4 hours (see Reaction Scheme 3).
  • the reaction solution was dialyzed against distilled water and freeze-dried to thereby obtain a paclitaxel-chitosan conjugate.
  • the amount of paclitaxel contained in the paclitaxel-chitosan conjugate was calculated.
  • the content of paclitaxel in the conjugate was 15-20% and 10-15% for chitosan of MW 3000 and 6000, respectively.
  • a paclitaxel-chitosan conjugate of the present invention (3000 and 6000 Da) was dissolved in dimethyl sulfoxide (DMSO) and diluted with a cell culture medium to prepare paclitaxel-chitosan conjugate solutions at a paclitaxel concentration of 0.01, 0.05, 0.1, 0.25, 0.5 and 1 D/mL.
  • B16F10 melanoma cells (KTCC) were cultured in a 96- well plate at a cell density of 5x10 cells/well for 24 hours and were treated with the above-prepared paclitaxel solution for 48 hours. Thereafter, the cell viability was measured using an MTT cell viability kit (Molecular Probe, Netherlands).
  • B16F10 melanoma cells were subcutaneously transplanted at a cell density of 5x10 cells/mice into a dorsal region of C57BL6 male mice (mean body weight: 25 g).
  • animals were divided into a treatment group and a control group.
  • mice were divided into a treatment group and a control group.
  • mice were divided into a treatment group and a control group.
  • mice were divided into a treatment group and a control group.
  • Animals were given oral administration of the drug or physiological saline for about 30 days, starting on day 10 after tumor transplantation.
  • Paclitaxel and the paclitaxel-chitosan conjugate were administered to animals at a dose of 25 mg/kg for 5 days, with no administration for following two days.
  • the control group was administered physiological saline, paclitaxel and chitosan.
  • the size of tumor was daily measured using a calibrator. The tumor size was calculated according to the following Math Figure (2):
  • FIG. 4 is a graph showing an anti-cancer activity in mice with administration of paclitaxel and the paclitaxel-chitosan conjugate, respectively.
  • the paclitaxel-ad- ministered group exhibited no significant difference in the tumor size, as compared to that of the control group.
  • the group with the administration of the paclitaxel-chitosan conjugate of the present invention exhibited a significant decrease in the tumor size, as compared to the control group.
  • mice were also monitored simultaneously with measurement of the tumor size. When the tumor mass reached a size of more than 8000 mm , the animals were euthanized.
  • mice of the group with the administration of the paclitaxel- chitosan conjugate of the present invention exhibited a 100% survival rate for about 30 days, whereas the mice of the control group exhibited a 0% survival rate prior to 30 days.
  • a conjugate of the present invention exhibits excellent absorption rate and biocom- patibility in biological mucous membranes, particularly mucous membranes of alimentary canal (especially the gastrointestinal tract), in vivo degradability, and superior bioavailability even with oral administration, thus enabling treatment of diseases via oral administration of a drug.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Otolaryngology (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un conjugué comprenant une substance pharmacologiquement active liée de façon covalente à un polymère mucoadhésif ainsi qu'une méthode d'administration transmucosale d'une substance pharmacologiquement active faisant appel audit conjugué. Plus spécifiquement, la présente invention concerne un conjugué comprenant une substance pharmocologiquement active liée de façon covalente via un lieur à un polymère mucoadhésif; une composition pharmaceutique pour l'administration transmucosale d'un médicament, comprenant le conjugué susmentionné et un support pharmaceutiquement acceptable; ainsi qu'une méthode d'administration in vivo d'une substance pharmacologiquement active via une voie transmucosale, par liaison covalente de la substance active à un polymère mucoadhésif via un lieur. Le conjugué de la présente invention présente un excellent taux d'absorption et une excellente biocompatibilité au niveau des muqueuses biologiques, en particulier des muqueuses du tube digestif (notamment le tractus gastro-intestinal), une excellente dégradabilité in vivo, ainsi qu'une biodisponibilité supérieure même lors de l'administration orale, permettant ainsi le traitement de maladies par administration orale d'un médicament.
EP07701046A 2006-01-23 2007-01-23 Conjugué comprenant un composé pharmaceutiquement actif lié de façon covalente à un polymère mucoadhésif et méthode d'administration transmucosale de composé pharmaceutiquement actif faisant appel audit conjugué Withdrawn EP1973952A4 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20060006632 2006-01-23
KR1020060068804A KR100766820B1 (ko) 2006-01-23 2006-07-22 단백질 또는 펩타이드의 경점막 운반 시스템
KR1020060068801A KR100791414B1 (ko) 2006-07-22 2006-07-22 항암제에 대한 경점막 운반 시스템
PCT/KR2007/000403 WO2007083984A1 (fr) 2006-01-23 2007-01-23 Conjugué comprenant un composé pharmaceutiquement actif lié de façon covalente à un polymère mucoadhésif et méthode d'administration transmucosale de composé pharmaceutiquement actif faisant appel audit conjugué

Publications (2)

Publication Number Publication Date
EP1973952A1 true EP1973952A1 (fr) 2008-10-01
EP1973952A4 EP1973952A4 (fr) 2010-09-01

Family

ID=39719136

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07701046A Withdrawn EP1973952A4 (fr) 2006-01-23 2007-01-23 Conjugué comprenant un composé pharmaceutiquement actif lié de façon covalente à un polymère mucoadhésif et méthode d'administration transmucosale de composé pharmaceutiquement actif faisant appel audit conjugué

Country Status (4)

Country Link
US (2) US20070292387A1 (fr)
EP (1) EP1973952A4 (fr)
JP (2) JP2009508852A (fr)
WO (1) WO2007083984A1 (fr)

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010221209C1 (en) * 2009-03-06 2015-09-03 Tamarisk Technologies Group, L.L.C. Microencapsulated bioactive agents for oral delivery and methods of use thereof
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
HRP20211377T1 (hr) 2011-11-23 2022-01-07 Therapeuticsmd, Inc. Prirodne kombinirane hormonske supstitucijske formulacije i terapije
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
WO2014028657A1 (fr) 2012-08-15 2014-02-20 Mimedx Group, Inc Greffes de tissu placentaire renforcées et procédés de fabrication et d'utilisation de celles-ci
US9943551B2 (en) 2012-08-15 2018-04-17 Mimedx Group, Inc. Tissue grafts composed of micronized placental tissue and methods of making and using the same
US8940684B2 (en) 2012-11-19 2015-01-27 Mimedx Group, Inc. Cross-linked collagen comprising an antifungal agent
US8946163B2 (en) 2012-11-19 2015-02-03 Mimedx Group, Inc. Cross-linked collagen comprising metallic anticancer agents
US9155799B2 (en) 2012-11-19 2015-10-13 Mimedx Group, Inc. Cross-linked collagen with at least one bound antimicrobial agent for in vivo release of the agent
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9662355B2 (en) 2013-01-18 2017-05-30 Mimedx Group, Inc. Methods for treating cardiac conditions
US10206977B1 (en) 2013-01-18 2019-02-19 Mimedx Group, Inc. Isolated placental stem cell recruiting factors
US10029030B2 (en) 2013-03-15 2018-07-24 Mimedx Group, Inc. Molded placental tissue compositions and methods of making and using the same
US10335433B2 (en) 2013-04-10 2019-07-02 Mimedx Group, Inc. NDGA polymers and metal complexes thereof
US9446142B2 (en) 2013-05-28 2016-09-20 Mimedx Group, Inc. Polymer chelator conjugates
CN103333250A (zh) * 2013-06-24 2013-10-02 上海大学 一种生物安全性好的纳米荧光探针的制备方法
US20160158369A1 (en) * 2013-07-10 2016-06-09 Seikagaku Corporation Pharmaceutical composition for respiratory administration
EP3038630B1 (fr) 2013-08-30 2020-03-18 MIMEDX Group Inc. Compositions placentaires micronisées comprenant un chélateur
AU2015206236B2 (en) 2014-01-17 2020-02-20 Mimedx Group, Inc. Method for inducing angiogenesis
KR101768446B1 (ko) 2014-03-21 2017-08-17 애니젠 주식회사 신규한 엑세나타이드 유사체 및 그의 용도
CA2947767A1 (fr) 2014-05-22 2015-11-26 Therapeuticsmd, Inc. Formulations d'hormones substitutives combinees naturelles et traitement hormonal substitutif
ES2819210T3 (es) * 2014-05-31 2021-04-15 Univ Arkansas Bioconjugados de citocina-quitosano y métodos de uso de los mismos
CN104072765B (zh) * 2014-07-09 2017-07-28 中国科学院长春应用化学研究所 改性聚乙烯亚胺及其制备方法、药物‑基因载体系统及其制备方法
KR101616623B1 (ko) * 2014-07-24 2016-04-29 연세대학교 산학협력단 양이온성 고분자가 결합된 소수성 약물 및 음이온성 고분자가 결합된 친수성 약물을 포함하는 나노입자
EP3185918B1 (fr) 2014-08-28 2021-08-18 MiMedx Group, Inc. Greffe de tissu renforcée par collagène
CN104800858B (zh) * 2015-04-27 2017-11-21 中国医学科学院基础医学研究所 Hsp90抑制肽偶联物及其在肿瘤治疗中的应用
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
BR112018005737A2 (pt) 2015-09-23 2018-10-09 Genentech Inc anticorpos, polinucleotídeo, vetor, célula hospedeira, método para produzir o anticorpo, para reduzir ou inibir a angiogênese, para tratar um distúrbio associado à angiogênese, para inibir a permeabilidade vascular, composição, conjugado de anticorpo, proteína de fusão, para identificar uma alteração de resíduos, utilização do anticorpo, utilização do conjugado e utilização da proteína
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
JP2019513709A (ja) 2016-04-01 2019-05-30 セラピューティックスエムディー インコーポレーテッドＴｈｅｒａｐｅｕｔｉｃｓｍｄ， Ｉｎｃ． ステロイドホルモン薬学的組成物
CN117100691A (zh) * 2017-04-07 2023-11-24 赛可勒生物医学避孕法有限公司 粘液屏障性能的增强
CN107400180B (zh) * 2017-07-27 2019-07-19 大连民族大学 氧化还原响应壳聚糖-脂质体的制备方法和用途
US20210015933A1 (en) * 2018-03-30 2021-01-21 Seikagaku Corporation Bioactive carboxylic acid type compound-polymer conjugate, and method for manufacturing the same
JPWO2020067507A1 (ja) * 2018-09-28 2021-08-30 生化学工業株式会社 第１級アミン化合物又は第２級アミン化合物−酸性多糖コンジュゲートとその製造方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0725141A1 (fr) * 1993-10-18 1996-08-07 Tovarischestvo S Organichennoi Otvetstvennostju "Bioprogress" Procede de transformation genetique maitrise de la glande mammaire d'un animal et dispositif d'introduction de matiere genetique dans les canaux galactophores de la glande mammaire d'un animal
WO2001005434A2 (fr) * 1999-07-20 2001-01-25 Amgen Inc. Conjugues hyaluroniques acide-proteine, compositions pharmaceutiques et procedes correspondants
WO2001012230A1 (fr) * 1999-08-17 2001-02-22 Park Myung Ok Administration de peptides conjugues a des polymeres biocompatibles par voie transmuqueuse nasale
EP1080732A1 (fr) * 1998-05-22 2001-03-07 Daiichi Pharmaceutical Co., Ltd. Composites medicamenteux
US20050186174A1 (en) * 2003-12-10 2005-08-25 Bossard Mary J. Compositions comprising two different populations of polymer-active agent conjugates
WO2006042146A2 (fr) * 2004-10-07 2006-04-20 Emory University Conjugues mutifonctionnels de nanoparticules et utilisation de ceux-ci
EP1710257A1 (fr) * 2004-01-07 2006-10-11 Seikagaku Corporation Derive d'acide hyaluronique et medicament contenant ce dernier

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5554388A (en) 1989-02-25 1996-09-10 Danbiosyst Uk Limited Systemic drug delivery compositions comprising a polycationi substance
US5194594A (en) 1990-09-07 1993-03-16 Techniclone, Inc. Modified antibodies
JPH08104651A (ja) * 1993-03-10 1996-04-23 Yoshiyuki Koyama 経粘膜薬物運搬体及び高分子医薬複合体
WO1996009805A2 (fr) * 1994-09-23 1996-04-04 Zonagen, Inc. Immunostimulation induite par le chitosane
US5968972A (en) * 1995-10-26 1999-10-19 Baker Norton Pharmaceuticals, Inc. Method for increasing the oral bioactivity of pharmaceutical agents
JP4079481B2 (ja) 1997-06-27 2008-04-23 久光製薬株式会社 経皮または経粘膜薬物送達用デバイス
JPH11116499A (ja) * 1997-10-16 1999-04-27 Asahi Chem Ind Co Ltd 生理活性ペプチドを含有した経口投与用ナノスフェア
EP2138191A1 (fr) * 1998-01-05 2009-12-30 University Of Washington Amélioration du transport par l'utilisation d'agents de rupture de membranes
US6896519B2 (en) 1998-07-27 2005-05-24 Chen & Chen, Llc Method of oral transmucosal delivery of a therapeutic agent
ITMI20010347A1 (it) 2001-02-21 2002-08-21 Grisotech S A Complessi di immunoglobuline e polisaccaridi per assorbimento orale etrans-mucosale
WO2002067995A1 (fr) * 2001-02-26 2002-09-06 Council Of Scientific And Industrial Research Systemes d'excipient comprenant des conjugues de microparticules biodegradables de vitamine b12 pour administration per os de medicaments, de peptides/proteines et de vaccins
AU2001242732B2 (en) * 2001-02-26 2006-08-24 Council Of Scientific And Industrial Research Carrier systems comprising vitamin B12-biodegradable micro particulate conju gates for peroral delivery of drugs, peptides/proteins and vaccines
JP2002371010A (ja) * 2001-04-13 2002-12-26 Toray Ind Inc ラミニン様活性ペプチドと生分解性膜複合体による人工基底膜
KR100507968B1 (ko) * 2001-08-18 2005-08-17 한국과학기술연구원 자기집합체를 형성하는 항암제-키토산 복합체 및 그의제조방법
ITPD20020271A1 (it) * 2002-10-18 2004-04-19 Fidia Farmaceutici Composti chimico-farmaceutici costituiti da derivati dei taxani legati covalentemente all'acido ialuronico o ai suoi derivati.
US6815462B2 (en) * 2003-01-09 2004-11-09 Bioxel Pharma Inc. Carbohydrate derivatives of paclitaxel and docetaxel, method for producing same and uses thereof
JP2007502823A (ja) 2003-08-15 2007-02-15 キューエルティー・ユーエスエイ・インコーポレーテッド 接着性および生体侵食性の経粘膜薬物送達システム
EP1667681A4 (fr) 2003-10-03 2009-09-30 Astron Res Pvt Ltd Nouveau systeme d'administration transmucosale
WO2005054301A1 (fr) * 2003-11-14 2005-06-16 Chugai Seiyaku Kabushiki Kaisha Microparticules de polysaccharides reticulees, et procede de production
US20050175679A1 (en) 2004-02-10 2005-08-11 Michael Moshman Controlled release formulations
BR122019000248B8 (pt) * 2004-03-23 2021-07-27 Complex Biosystems Gmbh reagente de ligador de pró-fármaco de cascata polimérico
JP2006104287A (ja) * 2004-10-04 2006-04-20 Hokkaido Univ 共有結合によるグリコサミノグリカンと細胞増殖因子との結合化合物およびその製造方法。
JP2009508938A (ja) * 2005-09-22 2009-03-05 ハダシット メディカル リサーチ サーヴィスィズ アンド ディベロップメント リミテッド 治療上活性な化合物の結合体
US20070134332A1 (en) * 2005-11-21 2007-06-14 Medivas, Llc Polymer particles for delivery of macromolecules and methods of use

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0725141A1 (fr) * 1993-10-18 1996-08-07 Tovarischestvo S Organichennoi Otvetstvennostju "Bioprogress" Procede de transformation genetique maitrise de la glande mammaire d'un animal et dispositif d'introduction de matiere genetique dans les canaux galactophores de la glande mammaire d'un animal
EP1080732A1 (fr) * 1998-05-22 2001-03-07 Daiichi Pharmaceutical Co., Ltd. Composites medicamenteux
WO2001005434A2 (fr) * 1999-07-20 2001-01-25 Amgen Inc. Conjugues hyaluroniques acide-proteine, compositions pharmaceutiques et procedes correspondants
WO2001012230A1 (fr) * 1999-08-17 2001-02-22 Park Myung Ok Administration de peptides conjugues a des polymeres biocompatibles par voie transmuqueuse nasale
US20050186174A1 (en) * 2003-12-10 2005-08-25 Bossard Mary J. Compositions comprising two different populations of polymer-active agent conjugates
EP1710257A1 (fr) * 2004-01-07 2006-10-11 Seikagaku Corporation Derive d'acide hyaluronique et medicament contenant ce dernier
WO2006042146A2 (fr) * 2004-10-07 2006-04-20 Emory University Conjugues mutifonctionnels de nanoparticules et utilisation de ceux-ci

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ILLUM L ET AL: "CHITOSAN AS A NOVEL NASAL DELIVERY SYSTEM FOR PEPTIDE DRUGS" PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS, NEW YORK, NY, US LNKD- DOI:10.1023/A:1018901302450, vol. 11, no. 8, 1 August 1994 (1994-08-01) , pages 1186-1189, XP000570481 ISSN: 0724-8741 *
KRUM KAFEDJIISKI ET AL: "Synthesis and in Vitro Evaluation of a Novel Chitosan-Glutathione Conjugate" PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NE LNKD- DOI:10.1007/S11095-005-6248-6, vol. 22, no. 9, 1 September 2005 (2005-09-01), pages 1480-1488, XP019370937 ISSN: 1573-904X *
ORIENTI I ET AL: "Chitosan-indomethacin conjugates. Effect of different substituents on the polysaccharide molecule on drug release" ARCHIV DER PHARMAZIE, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM, DE LNKD- DOI:10.1002/ARDP.19963290505, vol. 329, no. 5, 1 January 1996 (1996-01-01), pages 245-250, XP008081220 ISSN: 0365-6233 *
SALAMAT-MILLER N ET AL: "The use of mucoadhesive polymers in buccal drug delivery" ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER BV, AMSTERDAM, NL LNKD- DOI:10.1016/J.ADDR.2005.07.003, vol. 57, no. 11, 3 November 2005 (2005-11-03), pages 1666-1691, XP025284004 ISSN: 0169-409X [retrieved on 2005-11-03] *
See also references of WO2007083984A1 *
TARKOWSKI ANDREJ ET AL: "Treatment of experimental autoimmune arthritis by nasal administration of a type II collagen-cholera toxoid conjugate vaccine", ARTHRITIS AND RHEUMATISM, vol. 42, no. 8, August 1999 (1999-08), pages 1628-1634, XP055057886, ISSN: 0004-3591 *
WEST KEVIN R ET AL: "Reversible covalent chemistry in drug delivery." CURRENT DRUG DISCOVERY TECHNOLOGIES, vol. 2, September 2005 (2005-09), pages 123-160, XP008124424 *
YOUHUA SONG ET AL: "SYNTHESIS AND DRUG-RELEASE CHARACTERISTICS OF THE CONJUGATES OF MITOMYCIN C WITH N-SUCCINYL-CHITOSAN AND CARBOXYMETHYL-CHITIN" CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 40, no. 10, 1 October 1992 (1992-10-01), pages 2822-2825, XP000324876 ISSN: 0009-2363 *

Also Published As

Publication number Publication date
US20070292387A1 (en) 2007-12-20
US20140256623A1 (en) 2014-09-11
JP2009508852A (ja) 2009-03-05
JP2012051946A (ja) 2012-03-15
JP5491485B2 (ja) 2014-05-14
EP1973952A4 (fr) 2010-09-01
WO2007083984A1 (fr) 2007-07-26
US20170252453A9 (en) 2017-09-07

Similar Documents

Publication Publication Date Title
WO2007083984A1 (fr) Conjugué comprenant un composé pharmaceutiquement actif lié de façon covalente à un polymère mucoadhésif et méthode d'administration transmucosale de composé pharmaceutiquement actif faisant appel audit conjugué
KR101444274B1 (ko) 약제복합체용 블록 공중합체 및 의약조성물
US6436912B1 (en) Drug complexes
EP2459226B1 (fr) Glyco-polysialylation de protéines autres que des protéines de coagulation du sang
US20060127310A1 (en) Amplification of biotin-mediated targeting
CA2145502A1 (fr) Conjugues d'alginate sources d'agents bioactifs
JP2003511349A (ja) 薬剤担体としてのポリ（ジペプチド）
JP2002543111A (ja) ポリマーを使用する葉酸で仲介された腫瘍細胞へのターゲッティングの増幅
JP2014051527A (ja) 制御された薬物送達のためのテザー基を有するポリマー−薬物コンジュゲート
CN101489592A (zh) 考布他汀的高分子量偶联物
WO2000074721A1 (fr) Vitamine pour therapie a double ciblage
WO2013067767A1 (fr) Conjugué médicamenteux de polyéthylèneglycol-oligopeptide d'acides aminés-irinotécan et composition médicamenteuse de celui-ci
CN109152846B (zh) 缀合物和缀合试剂
JP6947909B2 (ja) マルチアーム標的抗がんコンジュゲート
KR100766820B1 (ko) 단백질 또는 펩타이드의 경점막 운반 시스템
CA2892003A1 (fr) Composes cycliques de cyclodextrine modifies comptant exactement deux fractions hydroxyle substituees par un acide amine aux fins d'une administration de produit therapeutique
AU2011330701A1 (en) Novel conjugates for targeted drug delivery
TW201340982A (zh) 聚合物複合體、藥物組合物、治療或紓緩疾病或症狀的方法、診斷疾病或症狀的方法以及聚合物複合體的用途
CN109224082B (zh) 一种大分子前药纳米药物、制备方法及其应用
CN109776787B (zh) 多臂靶向偶联物
CN109776788B (zh) 叶酸受体靶向多臂偶联物
CN109265676B (zh) 一种叶酸聚乙二醇胆固醇脂质材料及其应用
KR20170001835A (ko) 당화합물(sugar chemical compound)-탁산화합물(taxane compound) 접합체를 포함하는 암의 예방 또는 치료용 약학적 조성물 및 이의 제조 방법
KR100481434B1 (ko) 약물복합체의제조방법
CN110652592A (zh) 叶酸靶向双载药纳米粒的制备与应用

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080721

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

A4 Supplementary search report drawn up and despatched

Effective date: 20100803

RIC1 Information provided on ipc code assigned before grant

Ipc: C07K 17/08 20060101AFI20070904BHEP

Ipc: C07K 17/10 20060101ALI20100723BHEP

Ipc: A61K 47/48 20060101ALI20100723BHEP

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20130408

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: C07K 17/10 20060101ALI20170308BHEP

Ipc: C07K 17/08 20060101ALI20170308BHEP

Ipc: A61K 47/61 20170101AFI20170308BHEP

INTG Intention to grant announced

Effective date: 20170331

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170811

RIC1 Information provided on ipc code assigned before grant

Ipc: C07K 17/10 20060101ALI20170308BHEP

Ipc: A61K 47/61 20170101AFI20170308BHEP

Ipc: C07K 17/08 20060101ALI20170308BHEP

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/61 20170101AFI20170308BHEP

Ipc: C07K 17/08 20060101ALI20170308BHEP

Ipc: C07K 17/10 20060101ALI20170308BHEP